EP0137444B1 - Verfahren zur Herstellung von 6(R)-(2-(8(S)(2,2-Dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on - Google Patents

Verfahren zur Herstellung von 6(R)-(2-(8(S)(2,2-Dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on Download PDF

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Publication number
EP0137444B1
EP0137444B1 EP84111759A EP84111759A EP0137444B1 EP 0137444 B1 EP0137444 B1 EP 0137444B1 EP 84111759 A EP84111759 A EP 84111759A EP 84111759 A EP84111759 A EP 84111759A EP 0137444 B1 EP0137444 B1 EP 0137444B1
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Prior art keywords
methylation
reduction
solvent
mevinolin
catalyst
Prior art date
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EP84111759A
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English (en)
French (fr)
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EP0137444A2 (de
EP0137444A3 (en
Inventor
Meyer Sletzinger
Thomas R. Verhoeven
Ralph P. Volante
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Merck and Co Inc
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Merck and Co Inc
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Publication date
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Publication of EP0137444A3 publication Critical patent/EP0137444A3/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • trans:cis tetrahydromevinolin was produced.
  • the desired trans compound could be isolated from this mixture only after extensive silica-gel column chromatographic purification. Attempts to improve this ratio were investigated using a variety of catalysts and solvents and lead to the novel process of the present invention.
  • the ratio of starting material to catalyst, by weight is about 3/1 to 6/1 and preferably about 4/1 to 5/1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)

Claims (9)

1. Ein Verfahren für die Herstellung einer Verbindung der Strukturformel:
Figure imgb0006
das in beliebiger Reihenfolge die Schritte umfasst der
(1) katalytischen Reduktion der zwei Doppelbindungen des Mevinolin-Moleküls mit einem Platin-auf-Aluminiumoxid-Katalysator in einem organischen Lösungsmittel unter Bewegen; und
(2) C-Methylierung der 2-Methylbutyryloxy-Seitenkette des Mevinolin-Moleküls durch Umwandlung des Mevinolin-Moleküls von der Lactonform in das Alkalimetallsalz des Dihydroxycarboxylats, Methylierung mit einem Alkalimetallamid und einem Methylierungsmittel, ausgewählt aus Methylchlorid, Methylbromid oder Methyljodid und Einstellung des pH's auf 3 bis 6 mit Mineralsäure gefolgt von Relactonisierung.
2. Das Verfahren nach Anspruch 1, worin die zwei Schritte in der Reihenfolge Reduktion gefolgt durch C-Alkylierung sind.
3. Das Verfahren nach Anspruch 1, worin
(1) der Reduktionsschritt einen 2-10% Pt(A1203-Katalysator verwendet; das Lösungsmittel ausgewählt ist aus Ethylacetat, Isopropylacetat, Hexanen und Methylenchlorid; der Wasserstoffdruck Atmosphärendruck oder höher ist und die Temperatur 15―40°C ist;
(2) der C-Methylierungsschritt mit Methyljodid oder Methylbromid in einem etherischen Lösungsmittel bei -50 bis -25°C in Gegenwart eines Alkalimetallamids durchgeführt wird, worin das Alkalimetall Natruim, Kalium oder Lithium ist und das Amid Diethylamid, Dimethylamid, Pyrrolidid oder Diisopropylamid ist.
4. Das Verfahren nach Anspruch 3, worin die zwei Schritte in der Reihenfolge Reduktion gefolgt durch Alkylierung sind.
5. Das Verfahren nach Anspruch 3, worin
(1) der Reduktionsschritt 5% Pt/AI203, Ethylacetat und 2,76 bar (40 psi) Wasserstoff bei 20-25°C verwendet; und
(2) der C-Methylierungsschritt Methyljodid oder Methylbromid in Tetrahydrofuran bei -35° bis -30°C in Gegenwart von Lithiumdiethylamid oder Lithiumpyrrolidid verwendet.
6. Das Verfahren nach Anspruch 5, worin die zwei Schritte in der Reihenfolge Reduktion gefolgt durch Alkylierung sind.
7. Ein Verfahren für die Herstellung der Verbindung der Strukturformel:
Figure imgb0007
worin R 2(S)-Methylbutanoyl oder 2,2-Dimethyl-butanoyl ist, das die katalytische Reduktion der Verbindung der Strukturformel:
Figure imgb0008
mit einem Platin-auf-Aluminiumoxid-Katalysator in einem organischen Lösungsmittel unter Bewegen umfasst.
8. Das Verfahren nach Anspruch 7, worin der Katalysator 2-10% PtJAI203 ist; das Lösungsmittel ausgewählt ist aus Ethylacetat, Isopropylacetat, Hexanen, Methylenchlorid und Mischungen davon, der Wasserstroffdruck Atmosphärendruck oder höher ist und die Temperatur 15-40°C ist.
9. Das Verfahren nach Anspruch 8, worin der Katalysator 5% Pt/AI203 ist, das Lösungsmittel Ethylacetat ist, der Wasserstoffdruck 2,76 bar (40 psi) ist und die Temperatur 20-25°C ist.
EP84111759A 1983-10-11 1984-10-02 Verfahren zur Herstellung von 6(R)-(2-(8(S)(2,2-Dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on Expired - Lifetime EP0137444B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US54095883A 1983-10-11 1983-10-11
US540958 1990-06-20

Publications (3)

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EP0137444A2 EP0137444A2 (de) 1985-04-17
EP0137444A3 EP0137444A3 (en) 1988-03-02
EP0137444B1 true EP0137444B1 (de) 1990-01-31

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EP84111759A Expired - Lifetime EP0137444B1 (de) 1983-10-11 1984-10-02 Verfahren zur Herstellung von 6(R)-(2-(8(S)(2,2-Dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on

Country Status (4)

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EP (1) EP0137444B1 (de)
JP (1) JPS60104083A (de)
DE (1) DE3481190D1 (de)
IE (1) IE57687B1 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820850A (en) * 1987-07-10 1989-04-11 Merck & Co., Inc. Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof
DE3884536T2 (de) * 1987-09-03 1994-04-28 Merck & Co Inc Hydrierverfahren zur Bildung von Di- oder Tetrahydro-HMG-CoA-Reduktase-Inhibitoren.
US5177104A (en) * 1990-04-03 1993-01-05 E. R. Squibb & Sons, Inc. 6-α-hydroxy derivatives of mevinic acids
US5089523A (en) * 1990-05-11 1992-02-18 E. R. Squibb & Sons, Inc. Fluorinated derivatives of mevinic acids
US5264455A (en) * 1990-07-06 1993-11-23 E. R. Squibb & Sons, Inc. Sulfur-substituted mevinic acid derivatives
US5286746A (en) * 1991-12-20 1994-02-15 E. R. Squibb & Sons, Inc. Sulfur-substituted mevinic acid derivatives
US5369123A (en) * 1992-10-09 1994-11-29 E. R. Squibb & Sons, Inc. Nitrogen-substituted mevinic acid derivatives useful as HMG-CoA reductase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033538A2 (de) * 1980-02-04 1981-08-12 Merck & Co. Inc. 6(R)-(2-(8'-Acyloxy-2'-methyl-6'-methyl (oder hydrogen)-polyhydronaphthyl-1')-äthyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, die Hydroxysäure-Form dieser Pyranone, pharmazeutisch unbedenkliche Salze dieser Säuren, Niederalkylester, durch Phenyl Dimethylamino oder Acetylamino substituierte Niederalkylester dieser Säuren, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische antihypercholesterinämische Zusammensetzung

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB885044A (en) * 1958-05-19 1961-12-20 Fmc Corp A process for the production of carvomenthene oxide
PT72394B (en) * 1980-02-04 1982-09-06 Merck & Co Inc Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics
EP0094443A1 (de) * 1982-05-17 1983-11-23 Merck & Co. Inc. 6(R)-(2-(8(S)(2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-Pyran-2-on, Verfahren zur Herstellung und diese enthaltende pharmazeutische Zusammenstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033538A2 (de) * 1980-02-04 1981-08-12 Merck & Co. Inc. 6(R)-(2-(8'-Acyloxy-2'-methyl-6'-methyl (oder hydrogen)-polyhydronaphthyl-1')-äthyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, die Hydroxysäure-Form dieser Pyranone, pharmazeutisch unbedenkliche Salze dieser Säuren, Niederalkylester, durch Phenyl Dimethylamino oder Acetylamino substituierte Niederalkylester dieser Säuren, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische antihypercholesterinämische Zusammensetzung

Also Published As

Publication number Publication date
EP0137444A2 (de) 1985-04-17
JPS60104083A (ja) 1985-06-08
IE57687B1 (en) 1993-02-24
IE842593L (en) 1985-04-11
DE3481190D1 (de) 1990-03-08
EP0137444A3 (en) 1988-03-02

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